Current Medicinal Chemistry - Volume 32, Issue 25, 2025

Glioblastoma is the most common type of brain cancer, with a prognosis that is unfortunately poor. Despite considerable progress in the field, the intricate molecular basis of this cancer remains elusive.

The aim of this study was to identify genetic indicators of glioblastoma and reveal the processes behind its development.

The advent and integration of supercomputing technology have led to a significant advancement in gene expression analysis platforms. Microarray analysis has gained recognition for its pivotal role in oncology, crucial for the molecular categorization of tumors, diagnosis, prognosis, stratification of patients, forecasting tumor responses, and pinpointing new targets for drug discovery. Numerous databases dedicated to cancer research, including the Gene Expression Omnibus (GEO) database, have been established. Identifying differentially expressed genes (DEGs) and key genes deepens our understanding of the initiation of glioblastoma, potentially unveiling novel markers for diagnosis and prognosis, as well as targets for the treatment of glioblastoma.

This research sought to discover genes implicated in the development and progression of glioblastoma by analyzing microarray datasets GSE13276, GSE14805, and GSE109857 from the GEO database. DEGs were identified, and a function enrichment analysis was performed. Additionally, a protein-protein interaction network (PPI) was constructed, followed by module analysis using the tools STRING and Cytoscape.

The analysis yielded 88 DEGs, consisting of 66 upregulated and 22 downregulated genes. These genes' functions and pathways primarily involved microtubule activity, mitotic cytokinesis, cerebral cortex development, localization of proteins to the kinetochore, and the condensation of chromosomes during mitosis. A group of 27 pivotal genes was pinpointed, with biological process analysis indicating significant enrichment in activities, such as division of the nucleus during mitosis, cell division, maintaining cohesion between sister chromatids, segregation of sister chromatids during mitosis, and cytokinesis. The survival analysis indicated that certain genes, including PCNA clamp-associated factor (PCLAF), ribonucleoside-diphosphate reductase subunit M2 (RRM2), nucleolar and spindle-associated protein 1 (NUSAP1), and kinesin family member 23 (KIF23), could be instrumental in the development, invasion, or recurrence of glioblastoma.

The identification of DEGs and key genes in this study advances our comprehension of the molecular pathways that contribute to the oncogenesis and progression of glioblastoma. This research provides valuable insights into potential diagnostic and therapeutic targets for glioblastoma.

Indole is considered the most promising scaffold for anticancer drug design due to its high bioavailability, unique chemical properties, and broad spectrum of pharmacological action.

Twelve novel thiazole-containing the 5-fluoro-1,3-dihydro-2H-indol-2-one derivatives as sunitinib analogs were designed and synthesized, and their anticancer activity was evaluated against the NCI-60 cancer cell lines.

The thiazole-contained 5-fluoro-1,3-dihydro-2H-indol-2-one derivatives were synthesized using Knoevenagel condensation of 1,3-thiazole-5-carboxylic acid 1. Their anticancer activities were evaluated by NCI-60 one-dose screen assay. The molecular docking studies were performed using AutoDock tools and the AutoDock Vina programs. The ADMETlab 2.0 web server predicted the physicochemical properties of compounds.

Among the synthesized new 5-fluoro-2-oxindole derivatives, compound 3g demonstrated high antitumor activity (GI>70%) against eight types of cancer: leukemia, breast cancer, ovarian cancer, lung cancer, melanoma, CNS cancer, renal cancer, and colon cancer. The most activity was observed against breast cancer (T-47D, GI=96.17%), lung cancer (HOP-92, GI=95.95%), ovarian cancer (NCI/ADR-RES, GI=95.13%), and CNS cancer (SNB-75, GI=89.91%). The molecular docking results of compound 3g demonstrated the possibility of inhibiting VEGF2 receptors as his potential anticancer mechanism. The physicochemical properties predicted for compounds 3f and 3g showed positive results.

Compound 3g demonstrated high in vitro NCI-60 anticancer activity against nine cancer types and showed cell growth inhibition against leukemia, CNS, and breast cancer at 6 - 31% higher than Sunitinib, and may represent the basis for further modification of the thiazole-containing analogs of the anticancer drug Sunitinib.

Breast cancer (BRCA) is one of the leading causes of cancer-related death in women. The improvement of the BRCA risk assessment method is of positive clinical significance. Although many clues showed the potential role of disulfidptosis in BRCA as a novel type of programmed cell death, whether disulfidptosis is involved in BRCA tumorigenesis remains unclear.

We used LASSO-univariate Cox analysis and multivariate Cox analysis to identify six disulfidptosis-related lncRNAs (DPLs) that correlated with BRCA clinical outcome and confirmed that these DPLs were independent prognostic factors for BRCA (YTHDF3−AS1, AC002398.1, AL451085.2, AC092718.4, AC097662.1 and AC053503.5). The BRCA risk prognosis model was subsequently established based on these DPLs.

After verifying the model reliability in predicting prognosis, immune infiltration and somatic mutation analysis showed significant differences in the immune microenvironment and mutation of DPLs by risk stratification. Immunotherapy response and drug resistance analysis suggest the reference value of DPLs in clinical individualized therapy.

The abnormal expressions of selected DPLs were further validated by the BRCA cell line experiment. Our results shed new light on the role of DPLs in BRCA.

Steroid-induced avascular necrosis of the femoral head (SANFH) is a typical refractory disease that often progresses irreversibly and has a high disability rate. Numerous studies have confirmed that abnormal osteogenic-adipogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs) is one of the major factors of SANFH. However, the mechanism remains to be elucidated.

This study aimed to investigate the mechanism and effect of the IFT80/Hedgehog-mediated osteogenic-adipogenic differentiation of BM-MSCs in SANFH.

Femoral head specimens of SANFH patients and femoral neck fractures (FNF) patients were collected to detect the expression of IFT80, Shh and osteogenic-adipogenic differentiation-related genes by immunohistochemistry (IHC), western blot (WB) and Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR). Based on the rabbit SANFH model, the mRNA expression and protein level of IFT80 and Shh were detected by RT-qPCR and WB. After the osteogenic/adipogenic differentiation based on rabbit BM-MSCs, the IFT80, Gli1, PPAR-γ, and Runx2 expression were detected. Differences in alkaline phosphodiesterase activity, calcium nodule, quantification/distribution of lipid droplets, expression of IFT80/Hedgehog axis, and the level of osteogenic-adipogenic associated factors were determined after IFT80 overexpression.

RT-qPCR, WB and IHC revealed that IFT80 and Shh lowly expressed in the osteoblasts and intra-trabecular osteocytes at the edge of trabeculae and in the intercellular matrix of the bone marrow lumen in the SANFH specimens. The Runx2 expression was low, while the PPAR-γ expression was high in both human specimens and animal models of SANFH, suggesting that the balance of osteogenic-adipogenic differentiation was dysregulated. Rabbit BM-MSCs with stable overexpression of IFT80 showed increased alkaline phosphatase activity after induction of osteogenic differentiation, increased calcium nodule production, and decreased adipogenesis after induction of adipogenic differentiation.

There is a dysregulation of the balance of osteogenic-adipogenic differentiation in SANFH. IFT80 may inhibit adipogenic differentiation while promoting osteogenic differentiation in rabbit BM-MSCs by activating the Hedgehog pathway.

Pathogenic viruses that cause large-scale global or regional outbreaks almost always contain class I fusion proteins. Although the viruses differ in morphology, they all require fusion protein-mediated virus-host cell membranes during the early stages of host cell invasion.

The CHR region and NHR region of fusion proteins can form the 6-HB structure to drive the fusion pore formation between viruses and host cells through metastable interactions. Here, we obtained bifunctional N-peptides with inhibitory activities against two viruses, HIV-1 and MERS-CoV, based on the sequences in the HIV-1 NHR region by constructing N-trimer conformation interacting with the CHR region.

This study demonstrates that N-peptides with the coiled triple helix structure obtained from the NHR region in 6-HB are able to target the CHR region and exhibit inhibitory activity against a variety of viruses.

Moreover, this strategy can be used to investigate antivirals against unknown viruses for future outbreaks.

To determine the cell types that promoted the progression of Parkinson's disease (PD) using the substantia nigra in the brain tissues derived from patients with PD and normal controls.

PD is an incurable neurodegenerative disease that threatens the physical activity of the aging population, and the complex molecular mechanisms remain be comprehensively elucidated.

To describe potential disease-promoting cell types in PD and to provide a theoretical basis.

Single-cell nuclear sequencing data of nine PD samples and control samples from Gene Expression Omnibus (GEO) were included, and heterogeneous cell subpopulations in the substantia nigra were identified by annotation analysis. Potential pathogenic cell subpopulations of PD were determined based on the expression data of marker genes. Cell differentiation trajectories and communication networks were generated by Pseudotime trajectory analysis and cell communication analysis. Furthermore, single- cell regulatory network inference and clustering (SCENIC) analysis was conducted to determine the regulatory network of transcription factor-target genes in PD.

Among the nine cell subpopulations classified, RELN+neuron 3 showed reduced abundance and dopamine secretion capacity in PD and was therefore considered as a promoter of PD pathogenesis and progression. The regulatory network of MSRA action was involved in the developmental process of cells in the central nervous system, indicating that MSRA and its targets might serve as potential therapeutic targets for PD. RELN+neuron 3 had two directions of differentiation, specifically, branch 1 exhibited a high apoptotic profile and branch 2 exhibited a high cell death profile. In addition, the intensity of EPHA and EPHB signaling was attenuated between RELN+neuron 3 and other cell subpopulations.

To conclude, this study identified a subpopulation of RELN+neuron 3 cells with markedly reduced abundance in the brain substantia nigra in PD. The MSRA-involved gene regulatory networks was considered as a novel therapeutic network for PD.

Infertility was often considered a female issue, but male infertility emerged significantly after the COVID-19 pandemic. Hence, assessments are crucial for planning policies on health care and family planning and reasons thereof post vaccinations.

The present study was a case-control, dual-centers, prospective study with normal sperm parameters. Semen samples collected by masturbation for idiopathic reasons were conducted at King Abdulaziz University with 133 samples, followed by molecular modeling via interaction between IZUMO1, Alpha2A adrenergic receptor, and Fibroblast growth factor receptor 2 protein with IgA antibody produced post vaccination/infection.

The infertile males under 30 (21%), 31-40 (50%), 41-50 (24%) and over 50 (5%), with altered sperm motility grades are A (8.45%), B (11.1%), C (15.8%), and D (59.8%) were reported. Liquefaction times range from 36 to 30 minutes by age, with abnormal sperm percentages between 43.85% and 46.33%. Protein molecular interaction between IZUMO1, Alpha2A adrenergic receptor, and Fibroblast growth factor receptor 2 protein with IgA antibody shows cumulative length of 25.354 Å, 39.049 Å, and 41.999 Å, respectively, with significant interaction between atoms chain, amino acid, marked variation in bond length.

Male infertility peaks at 31-40 years, with lowering in men aged 41-50 years, IgA antibody reduced sperm motility, causing immunogenic infertility exacerbated post-COVID-19 vaccination or infection. Interaction of IgA and various receptors produced stable interactive molecules of IgA and proteins on sperm, affecting motility, aliquefication, and abnormal sperm percentage disturbing the normal dynamics of sperm cells opening a new dimension of infertility among males.